Primary biliary cirrhosis (PBC) appears to be a model autoimmune disease. Abnormal immune mechanisms are being studied in this disease, but so far a disease-specific immunologic deficit has not been defined with certainty. Recently recognized defects of humoral immunity include: (i) Evidence for the existence of an expanded clone of activated B cells that synthesize mitochondrial antibodies with different antigenic specificities from those synthesized by normal B cells; and (ii) Detection of a serum factor, probably an abnormally immunoreactive IgM, which blocks the binding of C3b-opsonized erythrocytes by monocytes. The latter finding affords a potential explanation for the C3b-receptor specific clearance defect by fixed macrophages in PBC. Recently recognized defects in cellular immunity include: (i) A diminished ability of patient T cells to suppress immunoglobulin synthesis; (ii) The presence of increased numbers of circulating activated B cells; and (iii) Hyporeactivity of lymphocytes in the autologous mixed lymphocyte reaction, which normally leads to activation of suppressor T cells. To determine whether such abnormalities of lymphocyte function in PBC might be due to altered function of immunoregulatory T cell subpopulations, phenotypic and functional characteristics of T cells that have the CD4 antigen detectable (by monoclonal antibody) on their surface were examined. In contrast to normal subjects and patients with other liver diseases, patients with PBC were found to have defects in CD4+, Leu-8+ T cell-mediated suppression of immunoglobulin synthesis and mitogen-stimulated proliferation. These defects may play a central role in the defective immunoregulation found in this disease.